Clinical samples from patients with acute or chronic non-A, B, C, D, E hepatitis in the United States are being studied for biological, serological or molecular evidence of transmissible agents. Patients with fulminant non-A, non-B hepatitis remain a diagnostic enigma and may be infected with one or more previously unrecognized viruses. We are attempting to discover the etiology of this disease. Evidence for the existence of an additional water-borne hepatitis virus has come from sero-epidemiologic studies in India and Saudi Arabia. From 50-100% of hepatitis cases in sixteen epidemics of water-borne hepatitis were caused by HEV but one water-borne epidemic was caused by neither HAV nor HEV. Similarly, in Saudi Arabia, 13.4% of acute hepatitis in adults could not be diagnosed as hepatitis A-E and appeared to be transmitted by nonparenteral means. We are attempting to transmit an agent from clinical specimens of such patients. Some years ago, a hepatitis virus was reported to be transmissible from a non-A, non-B hepatitis patient to marmoset monkeys. The agent, called the GB agent, could be serially transmitted in marmosets and was partially characterized. Recently the GB agent was cloned and sequenced and shown to be distantly related to a previously unrecognized human virus discovered by others. Others have independently discovered an additional human virus. The GB agent and the newly discovered human viruses are being studied in primates and in vitro. The objectives of this project are to identify and characterize new etiologic agents of hepatitis and to develop useful assays for diagnosis of infection and seroepidemiologic studies. A long-term objective is the development of passive and active immunoprophylaxis for these human pathogens.